NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’sdisease

Edna Grunblatt • Peter Riederer

Received: 3 July 2014 / Accepted: 26 September 2014

� Springer-Verlag Wien 2014

Abstract Evidence suggests that aldehyde dehydroge-

nase (ALDH; E.C. 1.2.1.3) gene, protein expression and

activity are substantially decreased in the substantia nigra

of patients with Parkinson’s disease (PD). This holds

especially true for cytosolic ALDH1A1, while mitochon-

drial ALDH2 is increased in the putamen of PD. Similarly,

in Alzheimer’s disease (AD) several studies in genetic,

transcriptomic, protein and animal models suggest ALDH

involvement in the neurodegeneration processes. Such data

are in line with findings of increased toxic aldehydes, like

for example malondialdehyde, nonenal, 3,4-dihydrox-

yphenylacetaldehyde and others. Genetic, transcriptomic

and protein alterations may contribute to such data. Also

in vitro and in vivo experimental work points to an

important role of ALDH in the pathology of neurodegen-

erative disorders. Aims at investigating dysfunctions of

aldehyde detoxification are suitable to define genetic/

molecular targets for new therapeutic strategies balancing

amine metabolism in devastating disorders like PD and

probably also AD.

Keywords Aldehyde dehydrogenase � Alzheimer’s

disease � Gene variation � Parkinson’s disease � Proteomic �Transcription

Introduction

Aldehyde dehydrogenase (ALDH; E.C. 1.2.1.3) metabo-

lizes both physiological and pathophysiological relevant

aldehydes (Jackson et al. 2011). The removal of toxic

aldehydes seems to play a central role of ALDH in the

cells, while ALDH enzyme activity is also required for the

synthesis of retinoic acid, folate and betaine (Marchitti

et al. 2008). In addition to its central detoxification

functionality, by its involvement in the retinoic acid

synthesis, ALDH plays a role in the modulation of cell

proliferation, differentiation and survival (Marchitti et al.

2008). Extending this point, ALDH enzymes exhibit

functions that appear to be independent to their enzyme

activity, including absorption of ultraviolet irradiation in

the cornea by acting as a crystalline and binding to hor-

mones and other small molecules, including androgens,

cholesterol, thyroid hormone and acetaminophen (Jackson

et al. 2011).

To date, nineteen putatively functional genes were

identified in the human ALDH gene superfamily [Jackson

et al. (2011); www.aldh.org, the aldehyde dehydrogenase

gene superfamily resource center (Black and Vasiliou

2009)]. It was recognized not only that the ALDH gene

consists of a great variety of genes, but many of the ALDH

genes encode multiple mRNA splice variants (Black et al.

2009). Moreover, over one-hundred copy number

E. Grunblatt (&)

University Clinics of Child and Adolescent Psychiatry,

University of Zurich, Wagistrasse 12, 8952 Schlieren,

Switzerland

e-mail: edna.gruenblatt@kjpdzh.ch

E. Grunblatt

Neuroscience Center Zurich, University of Zurich and ETH

Zurich, Zurich, Switzerland

E. Grunblatt � P. Riederer

University Hospital of Wurzburg, Department of Psychiatry,

Psychosomatics and Psychotherapy, University of Wurzburg,

Wurzburg, Germany

P. Riederer

Visiting Researcher, Institute Cognitive Brain Sciences, NCGG,

Obu, Aichi, Japan

123

J Neural Transm

DOI 10.1007/s00702-014-1320-1

variations (CNVs) have been reported by the Database of

Genomic Variants (DGV, http://dgv.tcag.ca/dgv/app/home)

for the human ALDH gene with deletions, duplications and

inversions thus increasing the complexity of the functional

genetics and these act on enzyme activity and expression

(Jackson et al. 2011). Nevertheless, several phylogenic

analyses point to the importance of the gene since it goes

back to more than two-thousands million years in the

evolutionary tree (Rzhetsky et al. 1997; Strickland et al.

2011). The transcriptional profile of most ALDH genes

show spread expression in the brain, in particular, the

variants ALDH2 and ALDH1A1 (Fig. 1). Similarly to the

mRNA, most of the ALDH proteins have a wide tissue

distribution, with some distinct substrate specificity

(Vasiliou et al. 2004). The different variants of ALDH

proteins are found in different subcellular regions including

cytosol, mitochondria, endoplasmatic reticulum and

nucleus. In particular, in the central nervous system (CNS),

ALDH catalyzes the irreversible oxidation of 3,4-dihy-

droxyphenylacetaldehyde (DOPAL), a metabolite of

dopamine, to 3,4-dihydroxyphenylacetic acid (DOPAC), or

3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a

metabolite of norepinephrine and epinephrine, to 3,4-

dihydroxyphenylmandelic acid (DOMA) which can then be

further metabolized into homovanillic acid (HVA), or

vanillylmandelic acid (VMA), respectively (Fig. 2) (Dedek

et al. 1979; Lamensdorf et al. 2000). Several reports point

to the disastrous effects of dysregulation in ALDH activity,

causing to increase cytotoxicity, oxidative stress, energy

deficits, apoptosis and cell death (Marchitti et al. 2008).

Increasing evidence at the genetic, transcriptomic and

protein levels suggest the involvement of ALDH in the

mechanism associated with neurodegeneration, in particu-

larly in Parkinsons disease (PD) and Alzheimers disease

(AD) (Marchitti et al. 2008). The evidence for ALDH

alterations at various levels in both AD and PD will be

described in this review.

Genetic alterations

The mitochondrial ALDH2, a polymorphic enzyme respon-

sible for the oxidation of acetaldehyde to acetate, encoded

on chromosome 12, has been often described in Asian

population with intolerance to alcohol who carries the

inactive subunit, denoted ALDH2*2 (rs671) (Goedde et al.

1992; Yoshida et al. 1984). When even one component of

the tetramer of ALDH2*1 is replaced by ALDH2*2, its

binding ability with NAD?, a coenzyme, is reduced due to a

structural change, resulting in loss of the enzyme activity

(Larson et al. 2005). Therefore, ALDH2*2 may act in a

dominant-negative manner. Moreover, the reduced activity

of the mitochondrial ALDH2 causes accumulation of

acetaldehyde and 4-hydroxy-2-nonenal (HNE), which has

been proposed to be potentially linked with AD (Ohta and

Ohsawa 2006; Tanzi and Bertram 2001; Picklo et al. 2001;

Shoeb et al. 2014). Nevertheless, both in a recent meta-

analysis as well as in www.alzgene.org, the ALDH2 geno-

type GA/AA or the alleles A vs. G were not found to

associate with increased AD risk [odds ratio (OR) = 1.35

95 % confidence interval (CI) = 0.75–2.42; OR = 1.23

95 % CI = 0.72–2.11, respectively]. In addition, a recent

case–control study of Japanese population with or without

high alcohol consumption AD could not find any significant

association of the ALDH2*2 with AD risk (Komatsu et al.

2014). Similarly to the ALDH2, the mitochondrial

ALDH18A1 gene on chromosome 10, was studied for its

association with AD risk, but also did not result in signifi-

cant association (www.alzgene.org, rs4417206; OR = 0.88

95 % CI = 0.77–1.01).

To date, neither genome-wide association studies

(GWAS) nor single genetic association studies (www.

pdgene.org) have reported gene variation on any of the

ALDH genes as risk for PD. Nevertheless, Fitzmaurice

et al. have described that when combining genetic sus-

ceptibility with environmental factors, this increased the

risk to develop PD (Fitzmaurice et al. 2014). In more

details, the study investigated whether exposure to pesti-

cides, in particularly such known to inhibit ALDH activity,

is associated with PD in particularly when probands carry

the cluster 2 (haplotype of rs737280, rs968529,

rs16941667, rs16941669, rs9971942) of the ALDH2 gene.

Indeed they could demonstrate that exposure of ALDH-

inhibiting pesticides was associated with increased PD risk,

and the genetic variation in ALDH2 exacerbated PD risk

(Fitzmaurice et al. 2014). Nevertheless, since this is the

first report of such association, it would be important to

reproduce this finding in additional populations, as well as

to understand the functional effects of these particular

genetic polymorphisms.

Transcriptomic alterations

Several studies for the abundance of mRNA expression in

fetal and adult human tissue of the various ALDHs have

been reported. Stewart et al. reported higher expression of

ALDH1 mRNA in liver, kidney, muscle and pancreas, while

ALDH2 and ALDH5 mRNA expressed in additional regions

as heart and brain also at fetal stages (Stewart et al. 1996).

Nevertheless, recent studies using the whole genome tran-

scriptomic studies reported by the Allen Brain Atlas (ABA

http://www.brain-map.org; Fig. 1), as well as in the human

protein atlas (http://www.proteinatlas.org) demonstrate the

wide-spread expression of the different ALDH transcript in

the CNS as well as in periphery. From these highly sensitive

E. Grunblatt, P. Riederer

123

methods, the expression of ALDH2, ALDH1A1, ALDH1L1,

ALDH5A1, ALDH16A1 and ALDH18A1 mRNAs could be

detected in adult human brain (Fig. 1).

To date, there are no reports concerning gene expression

alterations for ALDH genes in the CNS of AD patients.

Whereas, in peripheral blood samples, several studies

report mRNA profiling of ALDH genes (Maes et al. 2009;

Grunblatt et al. 2010; Molochnikov et al. 2012). In both

reports, ALDH1A1 mRNA expression did not change in

AD compared to controls [see GEO data base GDS2601

Fig. 1 Expression patterns in

the human brain of the aldehyde

dehydrogenase (ALDH) gene

superfamily (according to Allen

Brain Atlas (ABA), http://

human.brain-map.org). The

expression patterns of 10 gene

variants (ALDH2, ALDH1A1,

ALDH1A3, ALDH1B1,

ALDH1L1, ALDH1L2,

ALDH3A1, ALDH5A1,

ALDH16A1 and ALDH18A1)

in 6 probands of the ABA cre-

ated by the Brain Explorer� 2

software show the mRNA

expression in various brain

regions (e.g. frontal lobe, hip-

pocampal formation, occipital

lobe, temporal lobe, striatum

etc.) as log2 intensity (red-high

to blue-low)

ALDH in Alzheimer and Parkinson’s disease

123

and supplementary data in (Grunblatt et al. 2010; Molo-

chnikov et al. 2012)], as well as no change in expression

profile for ALDH2 mRNA was observed (GEO GDS2601).

In PD, the first to report down-regulation of ALDH1

mRNA in SN of PD was by Galter and colleagues, who

studied the expression alterations in post-mortem SN and

ventral tegmental area of controls and PD using in situ

hybridization technique (Galter et al. 2003). Following

these findings, more specifically, the down-regulation of

ALDH1A1 mRNA was found by our group using genome-

wide transcriptomic assay in SN from PD patients com-

pared to controls (Grunblatt et al. 2004). Following this

report, many other groups could consistently confirm

ALDH1A1 down-regulation in the SN of PD patients

(Durrenberger et al. 2012; Grunblatt 2012; Kotraiah et al.

2013). In the last report by Kotraiah et al. the analysis was

extended to the various splice variants of ALDH1A1,

which all showed similar down-regulation (Kotraiah et al.

2013). Moreover, they demonstrated a new approach of

screening ALDH1A1 activators and inhibitors, which

could be a starting point for development of highly specific

activator compounds that may restore the metabolism of

DOPAL in PD (Kotraiah et al. 2013). Decreased levels of

ALDH1A1 have not been reported in the peripheral blood

initially (Scherzer et al. 2007) but in two of our studies

ALDH1A1 could be demonstrated as being part of a com-

bination of four genes having potential diagnostic value to

detect individuals at risk of developing PD (Grunblatt et al.

2010; Molochnikov et al. 2012).

Protein alterations

Similar to the transcriptomic patterns of the various ALDH

mRNAs, the ALDH protein-expression patterns are widely

spread in CNS and peripheral tissues (http://www.protei

natlas.org). Nevertheless, the mitochondrial ALDH2

enzyme was more intensively studied for its alterations in

expression and activity in AD or PD brains (Picklo et al.

2001; Michel et al. 2010, 2014), while some reports indi-

cate changes in ALDH1A1 (Werner et al. 2008; Mandel

et al. 2007) and ALDH1L1 (Serrano-Pozo et al. 2013).

Picklo et al. described a unique distribution of the mito-

chondrial ALDH2 expression in the gray matter in human

cerebral cortex, limited to glia in cerebral cortex and hip-

pocampus (Picklo et al. 2001). Additionally, the immuno-

reactivity was prominent in senile plaques, in which it was

significantly higher in temporal cortex of AD patients

compared to controls (Picklo et al. 2001). This was

hypothesized as a reaction to the stress induced by senile

plaques. In accordance, we could detect a significant

increase in ALDH2 activity in the putamen of AD patients,

while no difference was observed in frontal cortex com-

pared to controls (Michel et al. 2010).

Recently, activated astrocytes were found to be differ-

entially detected by the fact that these astrocytes express

both ALDH1A1 and glial fibrillary acidic protein (GFAP),

while resting astrocytes express only ALDH1A1 (Serrano-

Pozo et al. 2013). Consequently, higher number of activated

astrocytes was exhibited in temporal cortex of AD patients

compared to control, while total astrocytes and microglia

were similar in both groups (Serrano-Pozo et al. 2013).

In PD, similarly to the transcriptomic alterations of

ALDH1A1 mRNA (see transcriptomic chapter), several

studies in post-mortem human brain could detect a decrease

in the expression of the cytosolic ALDH1A1 protein in PD

patients compared to controls (Mandel et al. 2007; Werner

et al. 2008). More specifically, in dopaminergic neurons

(neuromelanin positive) of the substania nigra pars compacta

(SNpc) diminished immunohistochemical positive ALDH1

signals were demonstrated in PD patients compared to

controls (Mandel et al. 2007). Similarly, proteomic analysis

using 2D-PAGE and MALDI-ToF–MS of SN homogenates

from PD and controls brains, revealed decreased expression

of ALDH1 protein (Werner et al. 2008). In contrast to the

Fig. 2 Metabolism of dopamine (DA), norepinephrine (NE) and

epinephrine (EPI) with the detoxification via aldehyde dehydrogenase

(ALDH) of the toxic by-products 3,4-dihydroxyphenylacetaldehyde

(DOPAL) or 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). ADH

alcohol dehydrogenase, ALR/AR aldehyde reductase, COMT catechol-

o-methyl transferase, DBH dopamine-b-hydroxylase, DOMA 3,4-

dihydroxymandelic acid, DOPAC 3,4-dihydroxyphenylacetic acid,

DOPEG dihydroxyphenylethylene glycol, DOPET 3,4-dihydroxyph-

enylethanol, HNE 4-hydroxy-2-nonenal, HVA homovanillic acid,

MAO monoamine oxidase, MHPE 3-methoxy-4-hydroxyphenyletha-

nol, MHPG 3-methoxy-4-hydroxyphenylglycol, MOPEGAL 3-meth-

oxy-4-hydroxyphenylglycoladehyde, PNMT phenylethanolamine-N-

methyltransferase, ROS reactive oxygen species, VMA vanillylman-

delic acid

E. Grunblatt, P. Riederer

123

cytosolic isoform, an increased mitochondrial ALDH2

activity was reported in the putamen of PD patients com-

pared to controls, while no alteration was observed in frontal

cortex (Michel et al. 2014). These different protein and

activity profiles of the cytosolic and mitochondrial ALDH

isoforms could be due to the fact that different brain regions

were analyzed but also due to their different role in substrate

metabolism. It is known that ALDH2 and ALDH1A1 may

act on different substrates at different concentrations and

they respond differently to different inhibitors (Ryzlak and

Pietruszko 1987; Maring et al. 1985; Yoval-Sanchez and

Rodriguez-Zavala 2012; Song et al. 2011; Budas et al.

2010).

Cellular and animal models for AD and PD

Cellular models

Cellular models provide an excellent platform to test

hypotheses for mechanisms of action in pathological dis-

orders such as in neurodegenerative disorders including

AD and PD. In this manner, the hypothesis that the

ALDH2*2 mutant causes the neurons to have higher sus-

ceptibility to oxidative stress was tested. The effect of the

ALDH2*2 gene was tested in a rat pheochromocytoma

(PC12) cells in which the mutated gene was introduced

(Ohsawa et al. 2003). This resulted in suppression of

mitochondrial ALDH activity in the cells but not cytosolic

activity. These cells were highly vulnerable to exogenous

HNE, an aldehyde derivative generated by the reaction of

superoxide with unsaturated fatty acid (Ohsawa et al.

2003). Following this report, Legros et al. studied the

discontinuous effects of increased dopamine, as happening

in PD subjects after oral L-DOPA therapy, and inhibition

of ALDH activity using disulfiram in catecholaminergic

neuroblastoma SH-SY5Y cells (Legros et al. 2004). It was

demonstrated that there was a potentiation of dopamine and

disulfiram induced toxic effects on SH-SY5Y cells, that

occurred several hours after the production of the toxic

product, DOPAL (Legros et al. 2004). Lately, not only

DOPAL, the toxic metabolite of dopamine and norepi-

nephrine, but also other reactive aldehydes were investi-

gated in relation with ALDH activity. For example the

3-aminopropanal (3-AP), the metabolite of polyamine

metabolism, was described to cause cytotoxicity and cell

death in various cell models (Wood et al. 2007). Woods

and colleagues could confirm the cytotoxicity of 3-AP

using retinal ganglion cell cultures following with the

finding that the 3-AP is metabolized to b-alanine by ALDH

in these cells, in which any alterations may cause increase

in ‘‘aldehyde load’’ promoting neurodegeneration (Wood

et al. 2007). Moreover, knocking down another ALDH

subtype, the ALDH1A1 in concert with the E3 ligase

ubiquitin SKP1A caused an exacerbation of the SN-derived

mouse cell line (SN4741) vulnerability to MPP? and

neurotrophin deprivation (Fishman-Jacob et al. 2010;

Mandel et al. 2012).

Supporting the epidemiological report of pesticides

exposure as risk for PD which increases with ALDH hap-

lotypes (Fitzmaurice et al. 2014), it was demonstrated that

the widely used pesticide, benomyl, inhibits ALDH activity

in primary rat cell culture originating from SNpc (Fitz-

maurice et al. 2013). This inhibition leads to neurotoxicity

of the dopaminergic neurons which was probably due to

increased DOPAL production (Fitzmaurice et al. 2013).

Several reports have pointed to the toxic effect of HNE

and in particularly the conjugated form protein-HNE

adducts (Zhang et al. 2010). Moreover, protein-HNE

adducts were found to increase in CSF and dopaminergic

neurons in the SN in PD and colocalize in Lewy-bodies in

neocortical and brain-stem neurons in both PD and in

diffused Lewy body disease (DLBD) (Zhang et al. 2010).

In addition, increased free HNE was found in the hippo-

campus and amygdala of AD brains compared to controls

and protein-HNE adducts are associated with neurofi-

brillary tangles (Zhang et al. 2010). Therefore, the pro-

tective effect of overexpression of ALDH1A1 in SH-

SY5Y cells via reduction of HNE was investigated

(Zhang et al. 2010). It was demonstrated that over-

expressing ALDH1, the main enzyme metabolizing HNE,

protected against toxic events precipitated by oxidative

stress, e.g. reduced accumulation of protein-HNE adducts

and reduced expression of caspase-3, an apoptotic marker

(Zhang et al. 2010), points to the importance of ALDH

activity in cell survival. Similarly, Kong and Kotraiah

demonstrated that overexpressing ALDH1A1 in PC12

cells increased HNE toxicity, while inhibiting ALDH1A1

by disulfiram reduced its toxicity (Kong and Kotraiah

2012). Moreover, they could show that this was linked to

the fact that decrease or increased HNE-protein adducts

were formed, respectively. Additionally, 6-methyl-2-

(phenylazo)-3-pyridinol, an activator of ALDH1A1,

demonstrated cytoprotective effects in PC12 cells (Kong

and Kotraiah 2012). At the same line as Zhang and col-

leagues, Bai and Mei reported neuroprotective effects of

overexpression of the mitochondrial ALDH2 against HNE

neurotoxicity (Bai and Mei 2011). They could demon-

strate that overexpression of ALDH2 in primary rat hip-

pocampal neurons protected the neurons against HNE-

induced neurite damage, decreased caspase-3 protein

expression, decreased reactive oxygen species (ROS) and

decreased the disruption of mitochondrial transmembrane

potential (Bai and Mei 2011).

Recent data described the link between amyloid beta

peptide (Ab) toxicity and the mitochondrial ALDH2

ALDH in Alzheimer and Parkinson’s disease

123

activity (Solito et al. 2013). In human endothelial cell line

treated with Ab they could show loss of mitochondrial

membrane potential, increased cytochrome c release and

ROS accumulation, that were also associated with HNE

accumulation and decrease in ALDH2 activity (Solito et al.

2013). All these data point to the angiogenesis processes

also known to occur in AD. Moreover, after treatment with

Alda-1, a selective ALDH2 activator, these detrimental

effects were abolished, pointing to the importance of

ALDH2 activity (Solito et al. 2013).

Animal models

The use of animal models to study effects of genetic vari-

ations or neurodegenerative processes on behavior, move-

ments and neurophysiology is widely accepted as a platform

investigating CNS alterations. As in the cellular models,

several reports indicate the involvement of ALDH in neu-

rodegeneration. Similarly to the experiment conducted in

cell lines (Ohsawa et al. 2003), a mice model in which

ALDH2*2 was introduced, showed in cerebral cortex pri-

mary culture increased cell death when HNE was introduced

(Ohta and Ohsawa 2006). Furthermore, 18-months-old

ALDH2-deficient mice showed signs of neurodegeneration

such as atrophy of the hippocampus and already at 6 months

a decreased spatial cognitive ability that was increased even

further after 18 months (Ohta and Ohsawa 2006). In a fol-

lowing paper from this group, it was reported that the

transgenic mice had decreased ability to detoxify HNE in

their cortical neurons and accelerated accumulation of HNE

in the brain (Ohsawa et al. 2008). This was also expressed in

a shorter life span than control mice expressed with age-

dependent neurodegeneration and hyperphosphorylation of

tau (Ohsawa et al. 2008). Also the transgenic mice presented

cognitive impairment that correlated with the degeneration,

which accelerated by apolipoprotein E (APOE) knock-out

(Ohsawa et al. 2008).

In the rat model for PD, in which 6-hydroxydopamine

(6-OHDA) is injected to lesion the nigrostriatal dopami-

nergic neurons, it was shown to cause a significant reduc-

tion in striatal ALDH activity (Agid et al. 1973). Similarly,

a year earlier, a reduction of ALDH activity in the striatum

of cats after electrolytic lesion of nigrostriatal tract has

been reported (Duncan et al. 1972). A very recent publi-

cation by Stott and Barker has looked in the 6-OHDA

striatal lesion in mice in a time course of up to 12 days

after lesion (Stott and Barker 2014). Since the lesion was

done in the striatum they could observe a reduction in the

number of dopaminergic neurons in the SN in a delayed

manner after surgery. Concurrently to the loss of SNpc

dopaminergic neurons a reduction in the level of

ALDH1A1 expression was observed 6 days after lesion

(Stott and Barker 2014). It seems that this alteration was

partly due to the shift in the expression pattern, in which

ALDH1A1 was restricted to the nucleus, while nearly no

expression was found in cytoplasm or dendritic fibers of

SNpc dopaminergic neurons (Stott and Barker 2014).

In a mouse model in which ALDH1A1 was knocked out,

the influence of ALDH1A1 on the function and mainte-

nance of dopaminergic system was assessed (Anderson

et al. 2011). The growth and development of SN dopami-

nergic neurons were not affected by the absence of

ALDH1A1 in these mice, nor the protein expression of

tyrosine hydroxylase, dopamine transporter or the vesicular

monoamine transporter 2 were affected (Anderson et al.

2011). Nevertheless, extracellular dopamine levels were

significantly increased in ALDH1A1 null mouse, the effect

of amphetamine was altered as well as higher number of

tyrosine hydroxylase expressing neurons in the SN were

observed in comparison to wild-type mouse (Anderson

et al. 2011). Moreover, a double knock-out mouse model of

both cytosolic ALDH1A1 and mitochondrial ALDH2

exhibited age-dependent deficit in motor performance that

was alleviated by intraperitoneal L-DOPA treatment (Wey

et al. 2012). In addition, a significant dopaminergic neu-

ronal loss in the SN was found together with reduction of

dopamine and metabolites in the striatum of the double

knock-outs (Wey et al. 2012). Besides, they found con-

comitant increase of HNE and DOPAL in this mouse

model (Wey et al. 2012). Similarly, the ratio between

DOPAL and dopamine was shown to increase significantly

in the striatum of double knock-out mouse, pointing to the

increase in neurotoxicity which was similar in the striatum

of post-mortem PD patients (Goldstein et al. 2013).

Recently, in a senescence-accelerated P8 (SAMP8)

mouse model of aging, the effect of 6 months voluntary

wheel running was explored at the gene expression levels

(Alvarez-Lopez et al. 2013). One of the genes differentially

expressed due to exercise was ALDH1A2 (restored to

control levels) in addition to the beneficial effects such as

tremor signs abolishment and hippocampal revasculariza-

tion (Alvarez-Lopez et al. 2013).

Indirectly, Meyer et al. could demonstrate that HNE

metabolism diminishes with age in rat brain mitochondria,

pointing to the possible decrease in the activity of ALDH2

with age (Meyer et al. 2004).

Conclusions

Aldehydes are increased in the SN of patients with PD.

Reasons for this could be loss of gene expression of

ALDH1A1 causing loss of enzyme protein and activity.

Experimental in vitro and in vivo data point to the con-

clusion that loss of ALDH activity substantially increases

neuronal toxicity in the nigrostriatal tract accompanied by

E. Grunblatt, P. Riederer

123

significant increase in toxic aldehydes. In AD, ALDH2

seems to be decreased as shown by increased acetaldehyde

and HNE concentrations, while meta-analyses as well as

gene expression of ALDH genes do not give evidence for

ALDH changes. In contrast, immunoreactivity in plaques

as well as activity in putamen but not in frontal cortex is

increased. These findings are at variance to PD and suggest

different behavior of aldehyde induced pathology in these

neurodegenerative disorders.

All available information is in line with the suggestion

(1) to further elucidate the role of ALDHs in the pathology

of neurodegenerative disorders and (2) to strengthen efforts

to antagonize the loss of ALDH subtypes by developing

respective therapeutic strategies.

Conflict of interest The authors declare neither competing financial

interests regarding this review nor conflicts of interest in respect to the

content of the article.

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